Omeprazole, chemically 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole and its therapeutic uses are disclosed in European Patent No. 5129. Omeprazole is a well-known gastric acid secretion inhibitor, and is useful as an anti ulcer agent. Omeprazole has a stereogenic center at sulfur and therefore exist as two optical isomers such as R-omeprazole and S-omeprazole (esomeprazole).
The resolution processes of racemates of Substituted 2-(2-pyridinylmethylsulfinyl)-1H-benzimidazoles were for example disclosed in DE 4035455 and PCT Publication No. WO 94/27988. According to these processes chiral ether such as fenchyloxymethyl or chiral acyloxy methyl group such as mandeloyl- is introduced into the 1-position of benzimidazole ring of racemic sulfoxide compound to obtain a diastereomeric mixture, diastereomers are then separated and desired isomer is liberated from a separated diastereomer. The process requires either the preparation of fenchyloxymethyl chloride and then reaction with the racemic compound; or introduction of chloromethyl group on 1-position of benzimidazole ring, followed by reaction with the chiral auxiliary. We find that these intermediates are difficult to prepare and involve in many steps.
PCT Publication No. WO 02/098423 relates to an inclusion complex of (S)-omeprazole with cyclodextrins. The process comprises adding a cyclodextrin to an aqueous solution of a substantially pure optical isomer of a benzimidazole compound or a pharmaceutically acceptable salt thereof, and isolating the inclusion complex so formed from the solution.
The resolution of sulfoxide compounds including racemic omeprazole were described in PCT Publication No. WO 2004/002982. The method requires expensive reagents like titanium compounds, two chiral reagents namely diethyl-D-tartarate and L-Mandelic acid.
Enantioselective synthesis is described for example in Euro. J. Biochem. 166 (1987) 453 and U.S. Pat. No. 5,948,789. Disadvantages of these methods are that strict control of conditions is to be maintained and strict control of quantities of oxidizing agents is required for avoiding oxidation of desired sulfoxide to sulfone impurity. Moreover, these methods require expensive reagents like titanium isoproxide and diethyl-D-tartarate.
The alkaline salts of (S)-enantiomer of omeprazole (esomeprazole), the pharmaceutical preparations of these salts and the method of treatment of gastric acid-related diseases using them are disclosed in U.S. Pat. Nos. 4,738,974, 5,877,192 and 5,714,504.
PCT Publication No. WO 2004/099181 A1 described a barium salt of the (S)-enantiomer of omeprazole, process for preparing the said barium salt, pharmaceutical compositions comprising the salt and a method of treatment of gastrointestinal ulcers comprising administration of the salt.
PCT Publication No. WO 2004/099182 A1 described a zinc salt of the (S)-enantiomer of omeprazole, process for preparing the said zinc salt, pharmaceutical compositions comprising the salt and a method of treatment of gastrointestinal ulcers comprising administration of the salt.
PCT Publication No. WO 2006/120520 A1 described a strontium salt of esomeprazole and a process for preparing it, which comprises reacting esomeprazole free base or a sodium, potassium or lithium salt of esomeprazole with a strontium source.
PCT Publication No. WO 2005/105786 A1 disclosed a stereoselective process for preparing substituted sulfoxides, which comprises reacting racemic omeprazole with (S)-camphorsulfonyl chloride to form a diastereomeric mixture, separating the diastereomers by fractional crystallization followed by deprotection to give esomeprazole.
PCT Publication No. WO 2005/116011 A1 disclosed a process for stereoselective synthesis of substituted sulfoxides, wherein 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]thio]-1H-benzimidazole is reacted with (R)-camphorsulfonyl chloride to form a mixture of 1-(R)-camphorsulfonyl-5- (and 6-)methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridyl)methylthio]-1H-benzimidazole, oxidized to obtain a diastereomeric excess of 1-(R)-camphorsulfonyl-(5- and 6-)-methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl-(S)-sulfinyl]-1H-benzimidazole over 1-(R)-camphorsulfonyl-(5- and 6-)-methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridyl) methyl-(R)-sulfinyl]-1H-benzimidazole, the diastereomers are separated by fractional crystallization and the separated 1-(R)-camphorsulfonyl-(5- and 6-)-methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl-(S)-sulfinyl]-1H-benzimidazole is deprotected to give esomeprazole.
PCT Publication No. WO 2007/013743 A1 disclosed a process for preparing optically pure esomeprazole which comprises dissolving (S)-(−)-binol, a weak base and the racemic form of omeprazole in a mixture of a water-compatible organic solvent and water at a high temperature, cooling the mixed solution to crystallize the inclusion complex of esomeprazole and (S)-(−)-binol, and removing the (S)-(−)-binol moiety from the crystallized inclusion complex.
However, a need still remains for an improved and commercially viable process for preparing enantiomerically pure esomeprazole that should solve the aforesaid problems associated with processes described in the prior art, which will be suitable for large-scale preparation, in terms of simplicity, chemical yield and purity of the product.
The object of the present invention is to provide an improved and commercially viable process for preparation of substantially enantiomerically pure esomeprazole in neutral form or as a pharmaceutically acceptable salt or as its solvates including hydrates.